EP0352139A2 - Détection des antigènes ou anticorps - Google Patents

Détection des antigènes ou anticorps Download PDF

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Publication number
EP0352139A2
EP0352139A2 EP89307464A EP89307464A EP0352139A2 EP 0352139 A2 EP0352139 A2 EP 0352139A2 EP 89307464 A EP89307464 A EP 89307464A EP 89307464 A EP89307464 A EP 89307464A EP 0352139 A2 EP0352139 A2 EP 0352139A2
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Prior art keywords
tubes
micro
particles
antibodies
sample
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EP89307464A
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German (de)
English (en)
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EP0352139A3 (fr
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Pak Leong Lim
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
    • G01N33/585—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances with a particulate label, e.g. coloured latex
    • G01N33/587—Nanoparticles
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/5302—Apparatus specially adapted for immunological test procedures
    • G01N33/5304—Reaction vessels, e.g. agglutination plates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
    • G01N33/54333—Modification of conditions of immunological binding reaction, e.g. use of more than one type of particle, use of chemical agents to improve binding, choice of incubation time or application of magnetic field during binding reaction
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/0098—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor involving analyte bound to insoluble magnetic carrier, e.g. using magnetic separation

Definitions

  • the present invention relates to a method of, and to a kit for, detecting antigens or antibodies in samples, which samples may comprise body fluids or secretions or excretions, cells or tissue extracts, or culture media.
  • Antigen detection has long preoccupied immunologists working in diverse fields, ranging from food microbiology and experimental biology to, very importantly, the clinical sciences. Thus, tests are being increasingly employed to detect antigens in biological fluids for assisting with the diagnosis of infectious conditions, such as bacterial meningitis, typhoid fever and viral infections, and non-infectious conditions such as pregnancy and various hormonal disorders.
  • Radioimmunoassays employing isotopic labels were popular in the 1960's, in which reactions were originally performed in solution.
  • ELISA solid-phase enzyme immunoassays
  • a recently introduced variation of the RIA and ELISA systems is an immunoassay performed on a nitrocellulose membrane.
  • Simpler assays are available such as counter-immuneolectrophoresis, co-agglutination or slide latex agglutination, the methods most commonly used to detect antigens from cerebrospinal fluid specimens.
  • slide latex agglutination is probably the most widely used today, due to its simplicity, low cost and speed. This is used to detect, among others, bacterial antigens in cerebrospinal fluid, viral particles in stool, and hormones in urine.
  • a reagent comprising latex particles previously coated with an antibody or antigen is mixed with a small sample (usually less than 0.05 ml) of the test material on a slide or card, which is rotated or rocked gently for about five minutes.
  • the result is then read visually, based on the presence or absence of particle-clumping.
  • the main drawbacks of the method are its relative insensitivity by comparison with the ELISA, and the fact that interpretation of the end-point can be subjective. Some improvement in these aspects can be achieved by performing the test in a large test-tube rather than on a slide. However, this tube method is seldom used for routine diagnosis except sometimes in cases of pregnancy or rheumatoid arthritis, because a large sample volume (1 ml) and a long incubation period (at least 1 hour) are required. In the instances where this has been used, the test is performed singly in individual large tubes, and the reaction mixture is not shaken during incubation.
  • antibodies are often used as the marker of infection or of other clinical conditions including the various auto-immune disorders.
  • the total concentration of antibodies of a particular specificity in a serum sample is usually determined.
  • diagnosis can be made more reliably if a particular class only of the antibodies present is measured.
  • IgM antibodies are used, since these appear during the acute phase of the infectious disease and then usually disappear, unlike the IgG antibodies, when the infection is terminated.
  • antibodies of other classes can also be diagnostically relevant.
  • IgE antibodies were found in a study to be a better indicator of cytomegalovirus infection than IgM antibodies, while the presence of circulating IgA antibodies to the VCA antigen of Epstein-Barr virus is strongly correlated with the presence of nasopharyngeal carcinoma in a person.
  • the methods used for antibody detection are similar to those used for detecting antigens.
  • the method most frequently used for determining class-specific antibodies is the ELISA, while RIA and immunofluorescence cytology are sometimes used.
  • Conventional latex agglutination methods do not permit such a determination.
  • antigen-coated latex particles have been used in an isolated instance to detect IgM antibodies against Rubella virus in a format based not on agglutination but on traditional solid-phase ELISA. The test was performed on microplates, and results were based on the settlement pattern of the latex particles in the microplate wells.
  • a method for the detection of antigens or antibodies in a liquid sample in which particles coated with antigen or antibody and having a diameter of from 50 to 1500 nm are used as the indicator reagent and are added to a set of micro-tubes containing the liquid sample in which antibody or antigen is to be detected, and in which method the tubes are incubated at ambient temperature with thorough mixing for a minimum period of 1 minute and sufficient to cause particles of the reagent to change if any of said antibody or antigen to be detected is present in the sample.
  • a diagnostic kit for use in the detection of antigens or antibodies in a liquid sample which kit comprises a set of micro-tubes for containing a said sample, and includes an indicator reagent comprising particles coated with antibodies or antigens responsive to the antigono or antibodies respectively to be detected in a said sample and having a diameter of from 50 to 1500 nm.
  • the particles used for coating with antibody or antigen are monodisperse microspheres, which are composed, for example, of latex (e.g. styrene-butadiene copolymer, polystyrene, styrene-divinylbenzene copolymer or acrylic copolymer), or of a sol of gold or other materials, or mixtures of two or more thereof.
  • latex e.g. styrene-butadiene copolymer, polystyrene, styrene-divinylbenzene copolymer or acrylic copolymer
  • the particles are preferably monosized.
  • various different colours of particles can be used, but preferred colours are red, blue, green and yellow.
  • the particles are used as a suspension thereof either in a liquid carrier medium or directly in the liquid sample under assay.
  • concentration of the particle suspension used in the assay may vary from 0.001% (final, w/v) (for instrumental reading) to 0.2% (for visual examination). For most assays in which the results are read visually, a preferred concentration is from 0.01 to 0.08%, using particles preferably about 800nm in diameter.
  • the set of micro-tubes of the present invention is specially designed and is preferably arranged in a single row comprising two or more tubes (preferably from three to twelve, e.g. eight).
  • the set of micro-tubes may be formed integrally, e.g. by casting from a single mould as a single unit or by machining tubes in a block of suitable material.
  • the set of micro-tubes may be comprised of individual micro-tubes made separately but thereafter held more or less immovably in a holder therefor that allows the reaction contained within the micro-tubes to be observed.
  • the set of two or more micro-tubes (of the same or different kinds) are thus physically linked or held together.
  • the material used for the set of micro-tubes is not of importance but should be at least translucent to allow the result of any reaction to be observed.
  • the set of micro-tubes is cast from a plastics material.
  • the specific shape and dimensions of the set of micro-tubes and of the individual tubes is not critical, it is important that the tubes be relatively small. If the tubes are small then only a relatively small volume of reagent and sample is required.
  • Each micro-tube may hold from 0.05 to 0.5 ml of reaction mixture.
  • the mouth of each tube is just wide enough for easy delivery of the test material and reagents, and the tube tapers downwardly to a narrow width so that the reaction mixture can attain reasonable height in the tube for easy visual examination.
  • the tube preferably has sufficient depth to allow for weak concentrations of the reagent particles to be used and seen.
  • the face of the set of micro-tubes is preferably flat for easy viewing of a reaction therethrough.
  • the reaction mixture in the set of micro-tubes be thoroughly agitated for at least a minimum period of time.
  • Such agitation causes any reaction to occur with far greater rapidity than is the case with the known method using individual large tubes.
  • the speed and intensity of the reaction depend on the manner in ant the force with which the reaction mixture is shaken, as well upon the duration of the agitation. Best results are thus obtained using a mechanical mixer such as the one described hereinafter, using the preferred conditions described and preferably at least a five minute incubation period. Similar assay sensitivities, however, may be achieved by manual mixing for similar or even shorter periods, but with such manual mixing it is preferred that the micro-tubes be allowed to stand for a certain time (e.g.
  • the agitation of the set of micro-tubes of the present invention may be done manually or by means of a suitable mixer or agitation device.
  • manual agitation this may conveniently be effected using the method as hereinbefore described, in which the set of micro-tubes is held in one hand and then repeatedly struck against the other hand.
  • a mixer there is no mechanical mixer available which is designed to accommodate the sets of micro-tubes of the present invention, for mixing the tube contents to the extent required.
  • a mixer it should be of a special design. It may be capable of holding one or more sets of micro-tubes.
  • the set(s) of micro-tubes may be mounted on one or both ends of an arm of the mixer which oscillates in a vertical plane about a horizontal axis.
  • the range of the arm motion is at least 20 o (preferably 47 o ) above and at least 20 o (preferably 47 o ) below the horizontal.
  • the speed of motion is at least 50 rpm, preferably 160 rpm.
  • an electric mixer adapted to agitate the set of micro-tubes in a manner similar to that of the manual mixing device described hereinafter.
  • a device which mixes the contents of the tubes in a different way, e.g. by repeated tube inversions may be employed.
  • the kit of the present invention may include the following items:-
  • the kit is used and the method of the present invention performed, preferably in the following manner, preferably with all steps carried out at room temperature:-
  • test sample in e.g. 0.05 ml, suitably diluted if necessary, and with or without pretreatment
  • a sample e.g. 0.1 ml
  • the set of micro-tubes is then shaken either manually or mechanically to mix the contents thoroughly for a defined period or until the positive control shows the desired effect.
  • Manual mixing may be effected by shaking the tubes continuously for from one to five minutes and, if necessary, repeating the process after an interval of a similar or longer period. The process can be repeated again for a few more times till a total time of e.g. from five to thirty minutes has elapsed.
  • Mechanical mixing may be continuously performed for from five to sixty minutes.
  • results may be read immediately after the agitation process, or, for better resolution and sensitivity in particle agglutination systems, after a further period in which the tubes merely stand to allow the aggregated particles to settle.
  • This subsequent incubation may be as short as a few minutes or, for greater sensitivity or for convenience, may be longer, e.g. 1 hour.
  • results may be read by the naked eye or by an electronic device, viewing through a face of the set of micro-tubes.
  • Visual examination is preferably based on a change of colour in the reaction mixture, achieved, for example, by using a combination of latex particles of two different colours so that reaction (settlement) of one type of particles leaves behind, in suspension, the particles of the other colour.
  • results may be based on particle clumping (flocculation) or particle settlement (turbidometry). Instrumental reading of the results may be effected in various ways depending on the type of particles used.
  • a colorimeter may be used to detect colour separation in multicoloured systems, whereas a spectrophotometer may be used to detect turbidometric changes in a monocolour system.
  • the particles may be made chemiluminescent or fluorescent, and that appropriate sensors based on such properties be used to detect the concentration of these particles.
  • test sample and the reagent particles are incubated together for a short time and the result then read on the presence or absence of agglutination (flocculation) in the reaction mixture.
  • the assay can be performed in two ways, based on (a) the direct binding of the antigen in the sample by the reagent (antibody-coated) particles or (b) the competition between the antigen in the sample and the reagent particles (antigen-coated in this case) for the reagent antibody (in soluble form).
  • the method is only applicable to samples which do not interfere with particle agglutination, such as urine, cerebrospinal fluid, buffer extracts of cells (including microorganisms) and tissues, and culture media.
  • the method can be used to detect bacterial antigens in culture broths (for identification purposes) or cerebrospinal fluid (for the diagnosis of meningitis), or specifically Trichinella spiralis antigens from larval extracts derived from pork tissue, for the diagnosis of swine trichinellosis.
  • the competition method can be used to detect human chorionic gonadotropin (hCG) in urine for the diagnosis of both normal and ectopic pregnancy. Details of this latter application are set out below.
  • the reagents were obtained from a commercially available pregnancy test kit used for performing slide latex agglutination tests (Gravindex ⁇ -hCG Slide Test for Pregnancy, Ortho Diagnostics Systems Inc, Raitan, NJ). These consisted of a suspension of latex particles which were covalently linked with hCG, and a solution or monoclonal antibodies specific for the ⁇ -subunit of hCG. Alternatively, these reagents could be prepared from base materials, e.g. using coloured latex particles (diameter, 800 nm) obtained from Rhone-Poulenic, Paris, hCG from Sigma Chemical Co., St. Louis, and monoclonal antibodies to ⁇ -hCG from Serotec, Oxford.
  • base materials e.g. using coloured latex particles (diameter, 800 nm) obtained from Rhone-Poulenic, Paris, hCG from Sigma Chemical Co., St. Louis, and monoclonal antibodies to ⁇ -hCG from Serotec, Oxford.
  • This method is modified from the one described in Example 1 for use with clinical specimens such as serum which interfere with latex agglutination or with samples that are voluminous. It consists of two stages. In the first, antibody-coated beads are used to remove the antigen of interest from the test sample, and the beads are subsequently washed and re-suspended in buffer. In the second stage, indicator latex particles coated with the appropriate antibodies are added to the bead suspension to detect the relevant adsorbed antigen in a procedure similar to that described in Example 1. It is imperative that the beads settle to the bottom of the tube at the end of the experiment, while unreacted indicator particles remain suspended. This may be achieved by using beads of large sizes (e.g. 2000 nm), or with magnetic properties so that they can be sedimented by use of a magnet. The indicator particles, on the other hand, are small (less than 1200 nm) and will only sediment when bound to the beads through antigen-antibody interactions.
  • the latex suspension will appear more yellow at the end of the experiment compared to the original suspension, which is greenish, since only the blue anti-RV indicator particles have been removed to the bottom of the tube.
  • the latex suspension appears blue, due to removal of the yellow anti-AV particles.
  • the results can be determined by turbidometric measurement as in Example 1. This latter application is described in the study below for the detection of Salmonella typhi lipopolysaccharide using an 0-9 monoclonal antibody produced in our laboratory.
  • Magnetic beads (Dynabeads M-450; diameter, 4500 nm) were obtained from Dynal, Skoyen, Norway, and latex particles (diameter, 800 nm) obtained from Sigma Chemical Co., St. Louis. Both particles were coated with a monoclonal antibody to Salmonella 0-9 antigen.
  • the antigen used, S. typhi lipopolysaccharide (LPS) was bought from Difco Co.
  • Table 2 shows the results of antigen detection using the proposed capture method, compared to the direct one-step procedure described in Example 1.
  • the direct method was more sensitive than the capture method when the same volume (0.1 ml) of test sample was used in both. However, with bigger volumes of test material, the sensitivity of the latter method increased significantly while that of the former remained the same.
  • the sensitivity of the capture method was influenced by the period of agitation/incubation at both stages of the test. Not illustrated is the greater inhibitory effect of serum on the direct method than on the capture method.
  • Table 2 Antigen detection by capture method a Vol test sample (ml) Antigen conc.
  • the method here is similar to that described in Example 2. Firstly, antibody (anti- ⁇ )-coated beads are used to remove total IgM antibodies from the test (serum) sample. Secondly, the presence of antibodies of a particular specificity in the adsorbed antibodies is determined using indicator latex particles coated with the relevant antigen. It is possible to detect antibodies of more than one specificity in the same test. This involves the use of indicator particles of different colours, each coated with a different antigen. For example, to determine whether the cause of viral hepatitis in a patient is due to Hepatitis A virus (HAV) or Hepatitis B virus (HBV), HAV and HBV indicator particles coloured, say, blue and yellow, respectively, are added to the IgM-bound beads.
  • HAV Hepatitis A virus
  • HBV Hepatitis B virus
  • the resulting latex suspension at the end of the experiment will appear yellow compared to the greenish colour of the original or control suspensions, since the blue HAV indicator particles will have become bound to the sedimented beads. Conversely, if IgM anti-HBV is present, the latex suspensions become bluish.
  • the method of the present invention was used in the study described below for the detection of IgM antibodies to Trichinella spiralis in mouse sera.
  • the Graph of Figure 8 shows the results of specific IgM detection by the proposed method.
  • the results were read using a spectrophotometer set at a wavelength of 400 nm, and are expressed as a % of the turbidity observed in control, unreacted latex suspensions. A decrease of 20% or more in turbidity is discernable by eye.
  • serial dilutions of nine serum samples were examined in the test. If 80% turbidity is used as the cut-off level, then six of the samples were positive in the test, with titres of specific IgM antibodies ranging from 1:50 to 1:600. There was good correlation with results obtained of these sample by an enzyme-linked immunosorbent assay.
  • Figs 1 and 2 Referring firstly to the sets of micro-tubes shown in Figs 1 and 2, it is believed that the Figures are essentially self-explanatory.
  • the set of micro-tubes is formed as an integral unit, e.g. by injection moulding.
  • Fig. 1 (b) individual micro-tubes are held or clamped in a holder therefor.
  • the micro-tubes are spaced at 1 cm centres and have a height of approximately 2 cm.
  • the width of the set of micro-tubes of Fig. 2 is 1 cm and the individual micro-tubes of the set each tapers from a wide mouth to a narrow base.
  • a simple holder and mixer for a set of micro-tubes according to the present invention.
  • the tube holder-mixer is designed to hold a set of tube of wide-ranging length (or even a single tube) so that the tubes can be shaken at one end of the holder-mixer while the other end is held by a hand.
  • the principle and procedure used are based on those used in the set of tubes.
  • the kit of the present invention differs from existing diagnostic kits which also utilise particles as reaction indicators in at least the following ways:-

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EP19890307464 1988-07-21 1989-07-21 Détection des antigènes ou anticorps Withdrawn EP0352139A3 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8817387 1988-07-21
GB8817387A GB8817387D0 (en) 1988-07-21 1988-07-21 Method for detecting antigens

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EP0352139A2 true EP0352139A2 (fr) 1990-01-24
EP0352139A3 EP0352139A3 (fr) 1991-01-16

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EP (1) EP0352139A3 (fr)
JP (1) JPH02140667A (fr)
AU (1) AU640346B2 (fr)
GB (1) GB8817387D0 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0396115A2 (fr) * 1989-05-03 1990-11-07 Abbott Laboratories Procédé de formation des agglutinats dans les échantillons de sang
EP0440193A2 (fr) * 1990-01-31 1991-08-07 Fujirebio Inc. Méthode d'essai immunochimique avec les items multiples
FR2664704A1 (fr) * 1990-07-11 1992-01-17 Bio Merieux Procede de detection d'une substance biologique dans un milieu liquide selon une technique de filtration permettant de retenir la substance biologique sur des particules ne traversant pas le filtre.
FR2858688A1 (fr) * 2003-08-04 2005-02-11 Gilbert Skorski Methode et dispositif pour mesurer plusieurs parametres biochimiques dans un echantillon

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102243228A (zh) * 2010-05-13 2011-11-16 南京神州英诺华医疗科技有限公司 一种新型的免疫学检测方法
JP6325833B2 (ja) * 2014-02-06 2018-05-16 富士フイルム和光純薬株式会社 磁性粒子の撹拌方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4419453A (en) * 1981-09-28 1983-12-06 The Dow Chemical Company Immunological agglutination assays with dyed or colored latex and kits
EP0247796A1 (fr) * 1986-05-22 1987-12-02 Unilever Plc Procédé de dosage immunologique en phase solide
EP0266278A1 (fr) * 1986-09-30 1988-05-04 Indicia Diagnostics Procédé et dispositif de dosage de substances d'intérêt clinique réactives immunologiquement

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4419453A (en) * 1981-09-28 1983-12-06 The Dow Chemical Company Immunological agglutination assays with dyed or colored latex and kits
EP0247796A1 (fr) * 1986-05-22 1987-12-02 Unilever Plc Procédé de dosage immunologique en phase solide
EP0266278A1 (fr) * 1986-09-30 1988-05-04 Indicia Diagnostics Procédé et dispositif de dosage de substances d'intérêt clinique réactives immunologiquement

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF IMMUNOLOGICAL METHODS, vol. 97, 1987, pages 153-158, Amsterdam, NL; S.G. HADFIELD et al.: "A novel coloured latex test for the detection and identification of more than one antigen" *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0396115A2 (fr) * 1989-05-03 1990-11-07 Abbott Laboratories Procédé de formation des agglutinats dans les échantillons de sang
EP0396115A3 (fr) * 1989-05-03 1991-07-24 Abbott Laboratories Procédé de formation des agglutinats dans les échantillons de sang
EP0440193A2 (fr) * 1990-01-31 1991-08-07 Fujirebio Inc. Méthode d'essai immunochimique avec les items multiples
EP0440193A3 (en) * 1990-01-31 1992-02-19 Fujirebio Inc. Immunochemical assay method with plural items
FR2664704A1 (fr) * 1990-07-11 1992-01-17 Bio Merieux Procede de detection d'une substance biologique dans un milieu liquide selon une technique de filtration permettant de retenir la substance biologique sur des particules ne traversant pas le filtre.
FR2858688A1 (fr) * 2003-08-04 2005-02-11 Gilbert Skorski Methode et dispositif pour mesurer plusieurs parametres biochimiques dans un echantillon

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EP0352139A3 (fr) 1991-01-16
AU3829189A (en) 1990-01-25
JPH02140667A (ja) 1990-05-30
AU640346B2 (en) 1993-08-26
GB8817387D0 (en) 1988-08-24

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